1. Field of the Invention
The present invention relates generally to reverse-turn mimetics, as well as to compositions and methods related thereto.
2. Description of the Related Art
Reverse-turns comprise one of three classes of protein secondary structure and display three (gamma-turn), four (beta-turns), or more (loops) amino acid side chains in a fixed spatial relationship to each other. Reverse-turns have proven important in molecular recognition events (Rose et al., Advances in Protein Chemistry 37:1-109, 1985) and have engendered a burgeoning field of research into small molecule mimetics (e.g., Hanessian et al., Tetrahedron 53:12789-54, 1997). Many mimetics have either been external turn mimetics, which do not allow for the display of all the physiologically relevant side-chains (e.g., Freidinger et al., Science 210:656-58, 1980), or small, conformationally mobile cyclic peptide derivatives (e.g., Viles et al., Eur. J. Biochem. 242:352-62, 1996). However, non-peptide compounds have been developed, which closely mimic the secondary structure of reverse-turns found in biologically active proteins or peptides. For example, U.S. Pa. Nos. 5,475,085, 5,670,155 and 5,672,681 to Kahn all disclose conformationally constrained, non-peptidic compounds which mimic the three-dimensional structure of reverse-turns. More recently, U.S. Pat. No. 5,929,237 to Kahn, U.S. Pat. No. 6,013,458 to Kahn et al., U.S. Pat. No. 6,184,223 to Kahn et al., and U.S. Pat. No. 6,294,525 to Stasiak et al. disclosed additional, highly constrained bicyclic heterocycles as reverse-turn mimetics. Nevertheless, as no one template can mimic every type of turn, there remains a need in the art for reverse-turn templates.
Analgesia has historically been achieved in the central nervous system by opiates and analogs, which are addictive, and peripherally by cyclooxygenase inhibitors that have gastric side effects. Substance P antagonists may induce analgesia both centrally and peripherally. In addition, substance P antagonists are inhibitory of neurogenic inflammation.
The neuropeptide receptors for substance P (designated as neurokinin-1) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. Such biological processes include sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (Pernow, Pharmacol. Rev. 35:85-141, 1983). Additionally, the neurokinin-1 and neurokinin-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci. 42:1295-1305, 1988).
The receptor for substance P is a member of the superfamily of G protein-coupled receptors. This superfamily is an extremely diverse group of receptors in terms of activating ligands and biological functions. In addition to the tachykinin receptors, this receptor superfamily includes the opsins, the adrenergic receptors, the muscarinic receptors, the dopamine receptors, the serotonin receptors, a thyroid-stimulating hormone receptor, the product of the oncogene ras, the yeast mating factor receptors, a Dictyostelium cAMP receptor, and receptors for other hormones and neurotransmitters (Hershey, J. Biol. Chem. 226:4366-73, 1991).
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2. In addition to substance P, the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1, neurokinin-2, and neurokinin-3 respectively.
More specifically, substance P is a neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence (Chang et al., Nature New Biol. 232:86, 1971; Veber et al., U.S. Pat. No. 4,680,283). In mammals, substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia, depending on dose and pain responsiveness of a mammal (Frederickson et al., Science 199:1359, 1978; Oehme et al., Science 208:305, 1980) and plays a role in sensory transmission and pain perception (Jessell et al., Advan. Biochem. Psychopharmacol. 28:189, 1981). For example, substance P is believed to be involved in the neurotransmission of pain sensations (Otsuka et al., “Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia” in 1982 Substance P in the Nervous System, Ciba Foundation Symposium, 91, 13-34 (published by Pitman); Otsuka et al., Trends Pharmacol. Sci. 8:506-10, 1987), specifically in the transmission of pain in migraine (Sandberg et al., J. Med. Chem. 25:1009, 1982; Moskowitz et al., Trends Pharmacol. Sci. 13:307-11, 1992) and in arthritis (Levin et al., Science 226:547-49, 1984; Lotz et al., Science 235:893-95, 1987). Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (Luber-Narod et al., poster C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul., 1992), and in disorders of bladder function such as bladder detrusor hyperreflexia (Lancet, 16th May, 1239, 1992). Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease (Mantyh et al., Neuroscience 25:817-37, 1988; Regoli in “Trends in Cluster Headache” Ed. F. Sicuteri et al., Elsevier Scientific Publisher, Amsterdam, pp. 85-95, 1987) and emesis (Trends Pharmacol. Sci. 9:334-41, 1988; Tatersall et al., Eur. J. Pharmacol. 250, R5—R6, 1993). It is also hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al., Lancet, Nov. 11, 1989; Gronblad et al., J. Rheumatol. 15:1807-10, 1988), and therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., Arthritis and Rheumatism 33:1023-28, 1990).
Tachykinin receptor antagonists are believed to be useful for treatment of pain, headache (especially migraine), Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases, such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Chrohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia (Maggi et al., J. Auton. Pharmacol. 13:23-93, 1993; Snider et al., Chem. Ind. 1:792-94, 1991). Other disease areas where tachykinin antagonists are useful include allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol. 66:1361-67, 1988), immunoregulation (Lotz et al., Science 241:1218-21, 1988; Kimball et al., J. Immunol. 141:3564-69, 1988; Perianin et al., Biochem. Biophys. Res. Commun. 161:520, 1989), postoperative pain and nausea (Bountra et al., Eur. J. Pharmacol. 249:R3—R4, 1993; Tattersall et al., Neuropharmacology 3:259-60, 1994), vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh et al., Proc. Natl. Acad. Sci. USA 85:3235-39, 1988) and, by arresting or slowing β-amyloid-mediated neurodegenerative changes (Yankner et al., Science 250:279-82, 1990) in senile dementia of the Alzheimer type, Alzheimer's disease and Downs Syndrome. Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) (Langdon et al., Cancer Research 52:4554-57, 1992). It is further-believed that tachykinin receptor antagonists have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement of suppression such as systemic lupus erythmatosus (EP Pat. No. 0,436,334), ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis (EP Pat. No. 0,394,989).
Substance P receptor antagonists may be useful in mediating neurogenic mucus secretion in mammalian airways and hence provide treatment and symptomatic relief in diseases characterized by mucus secretion, in particular, cystic fibrosis (Ramnarine et al., abstract presented at 1993 ALA/ATS Int'l Conference, 16-19 May 1993, published in Am. Rev. of Respiratory Dis., May 1993). Neurokinin-1 receptor antagonists alone or in combination with bradykinin receptor antagonists are also believed to be useful in the prevention and treatment of inflammatory conditions in the lower urinary tract, especially cystitis (Giuliani et al., J. Urology 150:1014-17, 1993). Furthermore, antagonists selective for the neurokinin-1 and/or neurokinin-2 receptor may be useful in the treatment of asthmatic disease (Frossard et al., Life Sci. 49:1941-53, 1991; Advenier et al., Biochem. Biophys. Res. Comm. 184:1418-24, 1992; Barnes et al., Trends Pharmacol. Sci. 11:185-89, 1993).
The following documents relate to compounds that are reported to exhibit activity as neurokinin antagonists: U.S. Pat. No. 6,194,406; U.S. Pat. No. 6,191,135; U.S. Pat. No. 6,177,450; U.S. Pat. No. 6,147,083; U.S. Pat. No. 6,114,315; U.S. Pat. No. 6,110,919; U.S. Pat. No. 6,063,926; U.S. Pat. No. 6,048,859; EP Pat. No 1,099,446; EP Pat. No 1,110,958; Published PCT WO200125219; and Published PCT WO200144200.
While significant advances have been made in the synthesis and identification of conformationally constrained, reverse-turn mimetics, there is still a need in the art for small molecules that mimic the secondary structure of peptides. There is also a need in the art for libraries containing such members, particularly those small templates capable of supporting a high diversity of substituents. In addition, there is a need in the art for techniques for synthesizing these libraries and screening the library members against biological targets to identify bioactive library members. Further, there is a need in the art for small, orally available inhibitors of neurokinins, for use in treating inflammatory diseases, central nervous system disorders, certain respiratory diseases, as well as other disorders. In particular there is a need for inhibitors of neurokinin-1, neurokinin-2, and neurokinin-3, for use in the treatment or prevention of various mammalian disease states such as, for example, asthma, cough, chronic obstructive pulmonary disease (COPD), bronchospasm, emesis, neurodegenerative disease, ocular disease, inflammatory diseases such as arthritis, central nervous system conditions such as anxiety, migraine and epilepsy, nociception, psychosis, and/or various gastrointestinal disorders such as Crohn's disease.
The present invention fulfills these needs and provides further related advantages.